NAXE

Inheritance Pattern: AR

Disease ID:MONDO:0020781

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NAXE and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2021. The NAXE gene encodes NAD(P)X epimerase that catalyzes the conversion of R-NAD(P)HX to S-NAD(P)HX, which are toxic cellular metabolites, so that S-NAD(P)HX can be reconverted to S-NAD(P)H by the dehydratase NAXD, thus preventing the accumulation of toxic metabolites. The NAXE gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2016 (PMID: 27616477). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four variants identified in two cases in two publications (PMIDs: 27616477, 32020600). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression and functional alteration in patient cells (PMIDs: 25613900, 27616477). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2021 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0020781

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NAXE* and *NAXE*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 22, 2024. The *NAXE* gene encodes NAD(P)HX epimerase that catalyzes the conversion of R-NAD(P)HX to S-NAD(P)HX, which are toxic cellular metabolites, so that S-NAD(P)HX can be reconverted to S-NAD(P)H by the dehydratase NAXD, thus preventing the accumulation of toxic metabolites. Toxic metabolites cannot act as electron carriers and inhibit other key dehydrogenases. The *NAXE* gene was first reported in relation to autosomal recessive *NAXE*-related primary mitochondrial disease in 2016 (PMIDs: 27616477, 27122014). *NAXE* has been associated with a single disease entity to date; encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy [OMIM# 617186]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NAXE*-related primary mitochondrial disease. Of note, *NAXE* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on March 24, 2021 (SOP v7), with a final classification of Limited. This current curation for the association with *NAXE*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 17 unique variants (10 missense, three nonsense, one frameshift, one in-frame deletion, and two splice site variants) identified in 15 unrelated cases from eight publications (PMIDs: 27616477, 27122014, 30022751, 31745726, 32020600, 34786481, 35819538, 36773198), although there have been at least 26 affected individuals from 18 families reported to date (additional case reports included in PMIDs: 34120322, 31758406, 34678889). Age of onset ranges from early in life to adulthood and the outcome is variable as some affected individuals die shortly after presenting and others alive at the time of report (oldest age 21 years). Disease progression is similarly variable. Clinical features in affected individuals include typically acute onset of neurologic deterioration/leukoencephalopathy, sometimes after febrile illness, as well as ataxia, seizures, and skin lesions. Brain imaging is consistent with leukoencephalopathy and/or LSS, and labs show elevated blood lactate levels. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in patient cells (PMID: 27616477), and a yeast model system (PMID: 30098110). In summary, there is definitive evidence to support the relationship between *NAXE* and autosomal recessive *NAXE*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 22, 2024 (SOP Version 10).